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PROGRESSION OF FIBROSIS AND THE FORMATION OF CIRRHOSIS
OF THE LIVER IN CHRONIC VIRAL HEPATITIS
Juraev Bobur Rakhmonovich Bukhara State Medical Institute named after
Abu Ali ibn Sina, Uzbekistan, Bukhara, A. Navoi St. 1 Phone number: +998 (65)
Abstract: The paper examines the literature data on factors affecting the
process of fibrogenesis and cirrhosis in chronic viral hepatitis. It is shown that the
course of fibrogenesis depends not only on the microorganism and the duration of the
infection, but also on the genetic predisposition and characteristics of the
macroorganism, the activity of the pathological process, the effects of hepatotoxic
agents (primarily ethanol), etc.
Keywords: chronic viral hepatitis, fibrosis, cirrhosis of the liver.
Chronic viral hepatitis (HCG) is an urgent problem of modern healthcare.
Currently, at least four pathotropic viruses are known to cause the development of
chronic hepatitis and cirrhosis of the liver (CP) — B, C, D and G. From a practical
point of view, the question of risk factors for the progression of fibrosis and the
formation of cirrhosis of the liver in viral hepatitis deserves attention. Features of the
microorganism. According to world statistics, the frequency of CP formation depends
on the causes of liver damage, including in viral hepatitis from the type of
hepatotropic virus. Thus, the frequency of CP formation in HBV monoinfection
reaches 4% [I], whereas in HBV/HDV mixed infection it increases to 40% [2]. In
HCV infection, CP, according to various authors, develops in 1.5 — 58% of cases [3,
4]. There are indications of the dependence of the formation of CP in HCG on the
genotype of the hepatotropic virus. Thus, J. N. Kao et al. [5] provide data on the
prevalence of the HBV genotype among patients with CP compared with
asymptomatic carriers (60 and 23%, respectively). H. Sumi et al. [6] also believe that
the HBV genotype is more associated with severe liver fibrosis (74/224 vs. 4/30 for
genotypes B and C, respectively). At the same time, according to M. F. Yuen. et al.
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[7], in patients infected with the HBV genotype, higher levels of AlAT and bilirubin
and lower levels of albumin were recorded, and, accordingly, higher mortality rates
due to decompensation of liver function compared to individuals with HBV infection
caused by geno type C. Brazilian researchers believe that infection, caused by
hepatitis B virus with a mutation in the pre core region, it leads to an increase in the
index of histological activity and the severity of liver fibrosis [8]. It is believed that
patients with HCV having genotype 1b have the most unfavorable course of the
disease, and CP is formed more often than with HCV caused by other genotypes of
the pathogen. In contrast, there is an opinion that accelerated fibrosis progression is
associated with not 1 HCV genotypes, in particular, with genotype 3 [9, 10]. However,
other authors believe that the formation of CP does not depend on the HCV genotype
[11]. In a study by M. Guido et al. [12] In children, the HCV gene type also did not
correlate with the degree of liver fibrosis. There are indications that in chronic
hepatitis D y patients with HDV genotype I, compared with patients with II, IV and
unclassified HDV genotype, complete remission is less often recorded (15.2 vs.
40.2%) and unfavorable outcomes of the disease (liver cirrhosis and hepatocellular
carcinoma) are more often noted (52.2 vs. 25%) [13]. The concentration (titer) of the
pathogen in blood serum and tissues is considered as one of the factors that aggravate
the course of hepatitis and lead to accelerated progression of liver fibrosis. According
to D. K. Wong et al. [14] the titers of HBV DNA detected in liver tissue correlate with
the concentration of HBV DNA in blood serum and with the degree of liver fibrosis.
It is believed that a significant progression of fibrosis in HCV is associated with the
concentration of HCV RNA in the blood serum exceeding 8 × 106 copies/ml [15]. At
the same time, the negative HCV RNA status of the blood serum of y patients with
HCV corresponds to the absence of progression of liver fibrosis [16]. According to
other data, viral load is not associated with the progression of fibrosis. Thus, N.
Saleem et al. [17] it is believed that the concentration of HCV RNA in the blood serum
does not correlate with the activity of the pathological process, nor with the degree of
liver fibrosis, nor with ca kim or another indicator of the Knodell histological activity
index. The course and outcomes of mixed infections of various hepatotropic viruses
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depend on these viruses. Thus, E. Sagnelli et al. [18] it is believed that mixed
HBV/HCV infection proceeds with more serious histological changes (including
fibrosis) compared to monoinfection with one of these viruses. The histological
activity index and the degree of liver fibrosis of y patients with HBV/HCV mixed
infection exceeded those of y individuals with HCV mono infection (3.5-1.1 and 3.0
- 1.1 points versus 3.5 - 0.8 and 2.3 - 1.1 points, respectively). At the same time,
according to S. Silva et al. [19] HBV infection does not lead to a worsening of the
course and severity of liver fibrosis and does not affect the effectiveness of antiviral
therapy in patients with HCV. It is also well known that a mixed infection of HBV
and HDV leads to a heavier clinical, laboratory and histological manifestations of the
disease and a significant increase in fibrosis and cirrhosis of the liver [20]. Mixed
infection with HIV leads to an acceleration of the processes of fibrogenesis and the
formation of CP in persons with HCV. It is believed that since the improvement of
HCV retroviral therapy, CP has become one of the main causes of death of HIV
patients. In a study by D. Fuster et al. [21] it was shown that y patients with mixed
HCV/HIV infection of the 3rd and 4th degrees of fibrosis were recorded significantly
more often than with HCV mono infection (46.7 and 12%, respectively). In contrast,
the Polish authors believe that in patients with HCV infection with HIV does not lead
to a deterioration of the histological picture of the liver, both with regard to the
inflammatory activity of the process and fibrosis [22]. The path of infection. Most
literary sources agree that the path of infection does not play a decisive role in terms
of fibrosis progression and CP formation. Despite this, R. R. Joya Vazquez et al. [23]
it is believed that the progression of fibrosis is associated with such infection
pathways as blood transfusion, extensive surgical interventions and hemodialysis. S.
Rerksuppaphol et al. [24] did not note any differences in the outcomes of NS infection
in y children depending on the path of infection (vertical or transfusion): y of all
patients (n = 31) during the follow-up period (on average, 13 years, range from 9 to
16.8 years), the disease proceeded without clinical symptoms; CP not a single patient
was formed. Features of the macroorganism. First of all, y adult patients have
indications of a high frequency of CP formation in y males. The cause of this
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phenomenon may be an inhibitory effect on the process of fibrogenesis of female sex
hormones. In the experiment, the administration of estradiol to rats exposed to a
hepatotoxic agent — carbon tetrachloride (CCC) led to a decrease in the level of
AsAT, AlAT, hyaluronic acid and type IV collagen in the blood serum, as well as to
a decrease in the content of activated stellate cells and collagen in the tissue liver [25].
The connection of the fibrosis process with female sex hormones is confirmed by the
fact that the progression of fibrosis in HCV was higher in post-menopausal women
and was accompanied by greater histological activity of the process. In post-
menopausal women who received hormone replacement therapy, the degree of
fibrosis increase was less (0.099 - 0.016 versus 0.133 - 0.006 units/year on the
METAVIR scale) and the corresponding y of women of the preclimacteric period
(0.093 - 0.012 units/year on the METAVIR scale) [26]. In accordance with this, sex
differences in the severity of liver fibrosis in HCV are manifested only in patients
younger than 50 years [27]. However, according to other data, the degree of liver
fibrosis is not related to gender [28]. In children with HCV, the degree of fibrosis is
also not related to gender [12]. However, there is evidence that the most severe course
of HBV CP is observed in girls [29]. There are racial and national differences in the
prevalence of severe fibrosis and cirrhosis of the liver. According to North American
authors, the severity of necro-inflammatory changes and liver fibrosis in HCV was
lower in Blacks compared to white Americans [30]. In another work, it was calculated
that y Spanish-speaking North Americans biochemical and histological activity of the
process in HCV exceeded those of y Blacks and white Americans; the frequency of
CP formation of y Spanish-speaking North Americans was higher than y Blacks and
tended to exceed that of y whites [31]. According to the Australian authors, among
the numerous ethnic groups living in Australia, pronounced liver fibrosis in CHB is
registered with the greatest frequency in persons of the so-called Mediterranean
ethnicity [2]. Data on genetic predisposition to increased fibrogenesis and the
formation of CP were also traced by the HLA system. According to A. L. Bondarenko
[33], the development of CP is associated with HLA antigens A1, B8 and haplotypes
A10, B8; B8, Cw3; B8, DR3; A1, B8, DR3; A1, B8, Cw2, DR5; A3, B8, Cw3, DR2.
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At work E. V. Volchkova and S. A. Potekaeva [34] in patients with HBV CP,
compared with HCV, HLA antigen B27 was significantly more common (71.4 and
9.5%, respectively). According to G. V. Volynets [29], in children with HCV, HLA
antigen A9 is associated with the most severe liver damage with the formation of CP.
Associations between chronic HDV infection and HLA antigens have been
established. In patients with chronic delta infection of Russian nationality, HLA B8
and B35 antigens are registered in the phenotype with increased frequency. The
presence of haplotypes A1/B8 and A1/B35 increases the risk of formation of both
HDV and HBV positive HCG. In persons of Kazakh nationality, delta infection is
associated with HLA B35 and B40 antigens, A2/B35, A1/B35 haplotypes. In patients
with HCV, the average values of the histological activity index were lower than in
patients with the DQB 1*0301 haplotype [3], whereas the DRB 1*0301 haplotype
was associated with progressive liver disease [37]. According to other data, although
patients with HCV CP compared with HCV had a lower frequency of occurrence of
the DRB 1*11 allele (5.6 vs. 14.5%) and a higher frequency — DRB1*03 and
DQ1*0201 (18.1 and 37.5% vs. 9.6 and 23.4%, respectively), ultimately, Class II
HLA alleles showed a weak association with the severity of liver fibrosis [3]. A
statistically significant relationship was found between the inheritance of a genotype
with a high production of TGF-1 (transforming growth factor -1) and angiotensin, and
the development of progressive liver fibrosis. The discovery of a reliable relationship
between the genotype with high angiotensin production and fibrosis suggests a
mediator role of angiotensin in extracellular matrix production in the liver [39]. It was
shown that in the experiment of y mice with a genetic deficiency of angiotensin I
receptors after the effect of a damaging factor on the liver (ligation of the external bile
ducts), a reduced content of various pro-inflammatory cytokines, profibrogenetic
cytokines (in particular TGF-1) and lipid peroxidation products in the liver tissue was
noted, and a lower severity of fibrotic changes in liver compared with the wild type
of mice [10]. To confirm the role of the renin angiotensin system in the process of
fibrogenesis, there is evidence that angiotensin converting enzyme (ACE) inhibitors
inhibit the processes of fibrogenesis. In a pilot study, it was shown that in patients
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with HCV who received ACE— losartan — 50 mg per day for 6 months, there was a
decrease in the severity of liver fibrosis compared to those who did not receive
losartan [11]. A mutation of the gene encoding the synthesis of TGF 1 at codon
position 10 is associated with the development of CP in CHB [22]. There is
information about the role of homo and heterozygous carriers of deficient S and Z
alleles of the alpha 1 antithrypsin gene in the formation of CP in HCV [23]. According
to other data, heterozygous carriage of the Z allele of the alpha-1 antitrypsin gene
does not affect the severity of liver fibrosis in HCV [14]. The frequency of HBV CP
development is associated with the genotypes of GSTM1 and GSTP1 Val (105)
glutathione 8 transferase, whereas the genotype of GSTT1 occurs with equal
frequency in patients with CP, HCG and "healthy" carriers of HBV [15]. Data on the
dependence of the fibroge process were obtained The risk and frequency of CP
development in HCV infection depends on the polymorphism of genes encoding the
synthesis of matrix metalloproteinases (MMP) — MMP 1, MMP 3 and MMP 9 —
enzymes directly involved in the processes of connective tissue remodeling [16]. High
levels of serum iron, ferritin and transferrin saturation coefficient are associated with
severe fibrosis and cirrhosis of the liver in HCV. In turn, with a high content of jelly
heterozygosity according to the gene of hereditary hemochromatosis is associated
with increased fibrosis in liver tissue in HCV. Moreover, heterozygous carriage of
mutation in the C282Y and H63D genes was found in the work of German authors in
patients with HCV in 4.2 and 21.3% of cases, respectively [7]. Iron overload leads to
an increase in the level of liver fibrosis in patients with thalassemia infected with
HCV, compared with patients with HCV without thalassemia and patients with
thalassemia uninfected with HCV [8]. According to other data, the serum ferritin level
and the iron content in the liver of the night tissue do not play a significant role in
liver damage in HCG [9]. Increased div weight is also a risk factor for the rapid
progression of liver fibrosis in HCV. Thus, in a study by A. D. Clouston et al. [50] it
was shown that in HCV, the average div mass index (div weight, kg/height 2, cm)
was higher in y patients with localized (28.4 - 4.7 kg/m2) or extensive (29.6 - 5.9
kg/m2) fibrosis than in y patients without fibrosis (25.5 - 3.7 kg/m2). Obesity and
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diabetes mellitus are directly related to the development of liver steatosis. Steatosis
can occur not only due to metabolic disorders, but also as a result of the cytopathic
effect of HCV (especially geno type 3) [1]. HCV ultimately disrupts lipid metabolism
and leads to impaired formation and release of very low-density lipoproteins and the
accumulation of triglycerides in hepatocytes. Another factor associated with the
development of steatosis in HCV infection is alcohol consumption. Steatosis,
regardless of other factors, is associated with the severity of inflammation and the
progression of liver fibrosis. Possible mechanisms of this effect are associated with
an increasing sensitivity of the liver affected by steatosis to oxidative stress and
cytokine-induced damage [2]. On the other hand, the Turkish authors did not find a
relationship between div mass index and the severity of liver fibrosis [3]. The
literature provides information that a high level of glucose in blood serum is
associated with an increased risk of significant liver fibrosis in HCV [1]. A correlation
between serum glucose levels and fibrosis was also found in children with HCV [54].
It has also been shown that insulin-resistant diabetes is associated with severe fibrosis
and cirrhosis of the liver in HCV [5]. The age of the patient at the time of infection.
There are indications of the importance of the age of infection of patients in the
pathogenesis of infection caused by hepatotropic viruses. Thus, chronic HBV
infection develops in 90-98% of children born to HBeAg positive mothers as a result
of perinatal infection. In infants, this figure decreases to 40-70%, in children aged 4-
6 years — to 10-40%, while in adults, HBV persistence occurs only in 5-10% of
individuals [5]. At the same time, there is an opinion that the chronization of the
process and the progression of fibrosis in adults is the higher the older the age of
infection of a person. Bye It is proved that the increase in liver fibrosis occurs faster
in persons infected after 40 years [2]. Among people infected with HCV during
hemotransfusion at the age of 50 years or more, the average duration of time from
hemotransfusion to the development of CP was 9.8 years, whereas among patients
infected with hemo transfusion before the age of 50, the average period of time before
the development of CP was 23.6 years prospective follow-up of patients did not
exceed 20 years. All calculations of the expected time of CPU formation are based on
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mathematical models and are, accordingly, likely. Therefore, the question of the
frequency and timing of CPU development remains open. Activity of the pathological
process. There is evidence that the growth of fibrosis and the formation of cirrhosis
of the liver in viral hepatitis occurs with a greater frequency in persons with increased
activity of the pathological process and a high degree of necro-inflammatory changes
in the liver. In accordance with this, the normal level of AlAT in the blood serum is
associated with the absence of progression of liver fibrosis [18], whereas the level of
AlAT, at least 1.5 times higher than normal, is associated with rapid progression of
liver fibrosis [6]. The Brazilian authors indicate that the level of aminotransferases
exceeding three norms is associated with 2-4 degrees of liver fibrosis [11]. According
to H. Fonlaine et al. [7] in HCV, an increase in the level of fibrosis was noted in y
13.3% of y patients with low and y 43.8% of patients with high indicators of the
activity of the pathological process. S. Herve et al the HCV RNA group of positive
individuals with normal serum AlAT levels (80 people) CP was observed
significantly higher than in the group of patients with elevated AlAT content (455
people) — 4 and 13%, respectively; at the same time, according to histological
examination of liver tissue, the progression of fibrosis in the second group of patients
was more pronounced, and the normal histological picture of the liver was more
common in the first group (9 and 1%, respectively). R. Mathurin et al. [2] in their
study, HCV patients were divided into two groups of 102 patients with normal (on
average, 25 units/l) and elevated (on average, 127 units/l) AlAT levels. The authors
found that in the first group, the degree of fibrosis (0.95 versus 1.8) and the average
level of fibrosis progression (0.05 versus 0.13 units on the METAVIR scale per year)
were lower than in the second. At the same time, there is an opinion that there is no
correlation between the level of cytokine transaminases and the activity of the
pathological process with liver fibrosis. I. Kyrlagkitsis et al. [3] in the examination of
99 patients with HCV with a normal Conclusion Thus, the data presented in the
literature show that, despite a fairly large number of studies concerning the problem
of CP in viral hepatitis, there is no definitive clarity on the factors contributing to
fibrogenesis and the development of CP. The available data are sufficiently
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contradictory. Nevertheless, from the presented material, it is possible to distinguish
the following factors that affect the course of fibrogenesis with the greatest frequency
in the works of different authors: etiology of viral hepatitis, mixed infection of various
hepatotropic viruses and HIV, genetic predisposition and features of the
macroorganism, duration of infection, activity of the pathological process and the
effect hepatotoxic agents (primarily ethanol). In the literature, only a few works are
devoted to the problem of the CPU of y children. We have previously shown that in
childhood, the formation of CP in the outcome of viral hepatitis, regardless of the
etiology of the disease, occurs at a fairly early time from the moment of infection, is
associated with increased activity of the pathologic process and does not depend on
the age and method of infection, the presence and nature of previous and concomitant
diseases, the genotype of the pathogen (with HCV infection) and the duration of the
infection [83]. The totality of the above data gives reason to believe that the process
of cirrhosis in chronic viral hepatitis is realized depending on the peculiarities of the
macroorganism in specific environmental conditions.
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